Diabetes is a major healthcare problem that is reaching crisis proportions, and new therapies are urgently needed. We have developed a long term, fully self-contained glucose monitoring sensor with battery-operated telemetry for implantation in subcutaneous tissues. The sensor would have unique applications in type 1 diabetes for hypoglycemia warning, insulin dosing, and control of the artificial pancreas. The sensor may also have application for glucose monitoring in type 2 diabetes, caloric and activity management in obesity, and prevention of type 2 diabetes in susceptible individuals. Development of this long term implantable glucose sensor has been underway for several years. Following extensive preclinical validations in the first phase of this project, including operation in animal implants of up to 520 days, in a second phase we demonstrated operation in a 6-month, FDA-cleared, first-in-human clinical trial. In this clinical trial, sensor/telemetry unis implanted in humans for six months demonstrated calibration stability for periods of up to one month at a time (the longest calibration interval examined). The clinical trial also revealed a need for several simple but valuable sensor design revisions, which have been completed and manifested in second generation devices now ready for human study. In the proposed project, we will verify acceptable performance of the second generation devices in a 6-month human clinical feasibility trial, which will include quantitative assessments of sensor accuracy and lag. The potential utility of the sensor for future application in closed-loop systems will also be evaluated. The long term implantable glucose sensor has an important role in the therapy for diabetes. The sensor we are developing has undergone systematic engineering analysis, extensive long term animal tests, and initial long term human clinical study. The proposed studies with the second generation sensor are designed to catalyze commercialization and accelerate delivery of the long term sensor into broad clinical practice.